Leishmaniasis exacts a staggering toll of mortality and morbidity on the developing world. Infection with parasites of the genus Leishmania causes a spectrum of disease in humans ranging from self-healing cutaneous lesions to life-threatening visceral infections. Two million new cases of leishmaniasis occur annually (1.5 million for cutaneous leishmaniasis and 500,000 for visceral leishmaniasis and over 350 million people are at risk of acquiring leishmaniasis, which is one of six diseases on the World Health Organization Tropical Disease Research (WHO TDR) list for priority research. The incidence of leishmaniasis may be increasing, and there is also growing interest in leishmaniasis in industrialized countries, in part due to the increase of Leishmania-HIV co-infection and the importance of the disease in current military operations. Leishmaniasis is most often treated by parenteral administration of toxic drugs such as pentavalent antimonials and amphotericin B, and drug resistance is becoming a problem. For the treatment of cutaneous leishmaniasis, a variety of drugs are frequently used, but none is effective against all species of the parasite that cause cutaneous disease. Herein we propose to investigate several niche sources of unstudied or understudied biodiversity in the search for new natural product chemotypes for treating leishmaniasis. Natural products represent 9 of 13 anti-parasitic drugs approved by the U.S. Food and Drug Administration in the past 25 years, highlighting the important role of this drug discovery resource for antileishmanial drug discovery research.